British Association of Dermatologists’ guidelines for the safe and effective prescribing of azathioprine 2011

Azathioprine is a thiopurine immunosuppressant drug that occupies an important place in the management of many autoimmune and inflammatory skin diseases. Its parent drug 6‐mercaptopurine (6‐MP), and the closely related 6‐thioguanine (6‐TG), were originally developed for their anticancer properties, but thiopurines as a class are now more widely used for their anti‐inflammatory and immunosuppressant effects. 6‐MP and 6‐TG have never found their way into routine dermatological practice and these guidelines relate to azathioprine and its extensive on‐ and off‐label applications for inflammatory dermatoses. Although azathioprine has been widely prescribed since the 1960s, there continue to be developments in understanding of drug action, pharmacogenetics and toxicology. These offer the potential for improved and individualized azathioprine prescribing, but have also created areas of controversy and resulted in contradictory information for clinicians. Nevertheless, a basic understanding of the issues relating to azathioprine metabolism and mode of action is important for the dermatologist, and should allow better explanation of treatment to patients with optimized prescribing and monitoring of therapy. The overall objective of the guideline is to provide up‐to‐date, evidence‐based recommendations for the safe and effective use of azathioprine. The document aims to update and expand on the previous guidelines by (i) offering a complete reappraisal of all relevant literature since 1966 and focusing on key developments over the past 5 years, in particular the applicability of thiopurine methyltransferase (TPMT) assessment to the clinical setting; (ii) addressing important, practical clinical questions relating to the primary guideline objective; (iii) providing guideline recommendations with an evaluation of their health economic impact; and (iv) discussing potential developments and future directions. The guideline is presented as a detailed review with highlighted recommendations for practical use in the clinic, in addition to updated patient information. The guideline working group consisted of dermatologists and a patient representative. The draft document was circulated to the British Association of Dermatologists (BAD) membership, the British Dermatological Nursing Group (BDNG), an immunologist and a hepatologist for comments and peer reviewed by the Clinical Standards Unit of the BAD (made up of the Therapy & Guidelines and Audit & Clinical Standards Subcommittees) prior to publication. This set of guidelines has been developed using the BAD’s recommended methodology1 and with reference to the Appraisal of Guidelines Research and Evaluation (AGREE) instrument.2 Recommendations were developed for implementation in the NHS using a process of considered judgment based on the evidence. PubMed, MEDLINE and EMBASE databases were searched up to January 2011 for randomized and nonrandomized controlled clinical trials, case series, case reports, open studies and research articles involving azathioprine and 6‐MP. Due to the expected high number of results in the EMBASE search, which has a particular emphasis on drug literature, additional search protocols were used specifically to target key areas such as thiopurine‐metabolizing enzymes and toxicity, as well as separating the results into predominantly dermatology‐ and gastroenterology‐based publications. Search terms and strategies are detailed in Appendix S1 (see Supporting information). Searches were also carried out in the Cochrane, National Institute of Health and Clinical Excellence (NICE), Database of Uncertainties about the Effects of Treatments (DUET) and Royal College of Physicians (RCP) databases. Additional relevant references were also isolated from citations in reviewed literature, as well as independent targeted searches carried out by each co‐author. All titles in the English language were screened, and those relevant for first‐round inclusion were selected for further scrutiny; the abstracts were then reviewed by all members of the working group and the full papers of relevant material were obtained following selection by common agreement. Specific selection criteria were not deemed necessary as the number of selected abstracts was relatively small (< 150) and there was consensus that the full papers were needed in most cases. The structure of the guidelines was then discussed and different co‐authors were allocated separate subsections. Each co‐author then performed a detailed appraisal of the relevant literature, and all subsections were subsequently collated and edited to produce the final guideline. This document has been prepared on behalf of the BAD and is based on the best data available when the document was prepared. It is recognized that under certain conditions it may be necessary to deviate from the guidelines, and that the results of future studies may require some of the recommendations herein to be changed. Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence. The proposed revision date for this set of recommendations is set for 2016; where necessary, important interim changes will be updated on the BAD website. This section aims to give an overview of the basis for the biological effects of azathioprine and introduce some concepts related to dosing and toxicity which will be detailed later in the guideline. 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toxicity of the has of past with for are of a in immunosuppressant the of in well of is well recognized of of not all as these may be the of the Association for the of the that all for immunosuppressant treatment should be for and prior to the of for should be considered in all also against in those are this should be of the for treatment with and a should also be to of all should be discussed with the experienced in the management of and considered on a on such as the of and Royal are recommendations for prior to but in those with should be is not necessarily a to the use of there is of the safe use of azathioprine and in is and has been with for of azathioprine in patients with should be those with in All patients may require treatment with azathioprine should be have those are about previous should be the of should prior to of azathioprine as the is the of Health against the also against of all to patients such as azathioprine. 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